OVERALL ? PROJECT SUMMARY/ABSTRACT Age related diseases causing dementia are an increasing global, social and economic catastrophe that mandates broad and aggressive research. Alzheimer?s disease (AD) is the most common cause of cognitive impairment in older adults and affects over 5 million people in the US alone. Vascular contributions to dementia and AD are increasingly recognized. However, the role of the cerebrovascular system in the pathogenesis of dementia and AD, and the underlying neurovascular mechanisms remain, to date, largely unknown and under- researched, representing a critical barrier in the field. The overall goals of this program are to advance current knowledge on the vascular contributions to dementia and AD, and establish whether the neurovasculature plays a major role in cognitive decline, and therefore is a key new therapeutic target to treat dementia and AD. This is a program project application with multiple projects, cores, institutions and investigators. It represents an integrated whole far greater than the sum of its parts. Each project and core complements the others so that a synergistic relationship among them is achieved with a common focus on goals of the program, namely to test the neurovascular hypothesis of AD. This hypothesis holds that cerebrovascular dysfunction and disruption in the neurovascular integrity underlies and contributes to the onset and progression of cognitive decline. We have enlisted established clinical and translational research groups that collectively bring significant expertise in all aspects of the research plan and each have contributed productively over many years to the study of dementia and AD. To test the ?neurovascular hypothesis?, the participating investigators will apply cutting-edge molecular and imaging methods. We will perform parallel studies with analogous measures in humans and rats in two AD genetic risk groups with the major genetic risk factors for late-onset AD, i.e., apolipoprotein E-?4 (APOE4) gene and early-onset autosomal dominant AD (ADAD), i.e., presenilin 1 (PSEN1) mutations that both develop early vascular dysfunction and significant cerebrovascular pathology, and in the rat model of AD (line TgF344-AD) that faithfully recapitulates the rich clinico-pathological spectrum of human AD including the presence of early vascular dysfunction and cerebrovascular pathology. Central to our approach is our commitment to take a new research direction with the overarching goal to provide an answer to the broader question; ?what is the role of the vascular system in the pathogenesis of dementia and AD?, and ?what is the prognostic and diagnostic value of neurovascular molecular and imaging biomarkers in predicting cognitive decline?. The relationship between neurovascular integrity, brain connectivity and cognitive function has not been explored. The collective expertise of the investigators, overall environment, preliminary results, and experimental design for each of the projects and supporting cores hold tremendous promise for the success of this program. We are confident that the proposed studies will have a significant impact on our understanding of pathogenesis, treatment, and early prevention of dementia and AD.